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Pathomechanisms of Heavy Metal Overload in ASD: History
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Contributor: Anna Błażewicz , Andreas M. Grabrucker

Toxic metals may impact brain development directly, as they are able to reach the brain tissue, or through a secondary effect of peripheral pathologies affecting the brain. Toxic metals may interfere with dozens of physiological processes such as DNA methylation, histone modifications, microRNA expression, changing protein properties, or affecting gut-brain signaling by altering the microbiota composition. The autism spectrum disorders (ASDs)-related effects may only occur during a person’s prenatal period. 

  • cadmium
  • lead
  • mercury
  • oxidative stress
  • lipid peroxidation
  • ASD

1. Oxidative Stress and Mitochondrial Dysfunction

Elevated levels of oxidative stress are a well-described feature of ASD [1][2][3][4][5]. The actions in mitochondria that result in the synthesis of adenosine triphosphate (ATP) naturally produce free radicals, also known as reactive oxygen species (ROS). Reactive nitrogen species (RNS) and radicals with carbon and sulfur centers are also produced [6]. As a result, small amounts of ROS in brain tissue should be regarded as normal, but large amounts that cause oxidative stress are harmful. Excessive free radical generation or insufficient cellular mechanisms to alleviate oxidative stress can contribute to elevated oxidative stress levels. The brain is particularly vulnerable to oxidative stress because of its high energy (ATP) requirements.
The brain is a lipid-rich tissue. Lipid peroxidation thus poses a particular threat to brain cells [6]. However, excess ROS also causes protein oxidation in addition to lipid peroxidation. Together, the two processes might be responsible for aberrant neurogenesis, synaptic signaling, plasticity, brain cell death, and functional deficits [7][8][9][10]. For example, oxidative stress may change brain-derived neurotrophic factor levels (BDNF) [11]. BDNF is a growth factor linked to the pathogenesis of ASD as a regulator of neurogenesis, neuron survival, and synaptic plasticity [12].
As underlying reasons for increased ROS in ASD, numerous studies implicate an increase in BBB permeability that results in neuroinflammation [13][14]. For example, it has been noted that exposure to mercury damages the BBB, exposing the CNS to undesired substances that might cause processes such as neuroinflammation [15]. Additionally, it has been suggested that excitotoxicity caused by aberrant glucocorticoid receptor signaling, and altered N-methyl-d-aspartate (NMDA) receptor signaling contribute to ROS [16][17][18].
One defense mechanism that can lower ROS levels is the antioxidant response system. It works by activating antioxidant enzymes such as catalase (CAT), glutathione peroxidase, glutathione reductase, glyoxalase, and superoxide dismutase (SOD) [19]. Interestingly, SOD enzymes require essential trace metals, for example, copper and zinc (Cu-Zn SOD). Low-molecular-weight antioxidants such as glutathione, uric acid, ascorbic acid, and melatonin are used in the second stage of the antioxidant response system. These primarily act through scavenging metals [20].
Elevated levels of oxidative stress are also a well-described feature of heavy metal exposure. Mercury is one of the toxic metals that raises oxidative stress levels and harms mitochondria [21][22][23]. Mercury can inhibit sulfhydryl-containing enzymes by forming a covalent bond with sulfhydryl (thiol) groups [24]. Similarly, other proteins and non-protein molecules, such as glutathione (GSH), may be impacted by the direct chemical interaction between MeHg and thiol [24]. Due to GSH’s function as an antioxidant, if GSH levels fall, oxidative stress rises [25]. However, it has also been demonstrated that MeHg directly interacts with nucleophilic protein groups to cause oxidative stress [19]. In addition, mercury exposure also results in glutamate excitotoxicity [26]. MeHg increases glutamate levels in the synaptic cleft by inhibiting glutamate re-uptake into synaptic vesicles and promoting spontaneous release, according to in vitro and animal studies [26][27][28][29].
Abnormally high glutamate concentrations in the synaptic cleft can cause NMDA-type glutamate receptor (R) overactivation. Apart from direct consequences on synapse formation, stability, and function, this raises the amount of sodium and calcium that enters neurons through NMDARs. In response, excessive intracellular calcium will again boost oxidative stress (for example, by translocation into mitochondria) [30]. Because astrocytes help remove the glutamate from the synaptic cleft, mercury injury to astrocytes exacerbates excitotoxicity [31].
Excessive cadmium concentrations also result in oxidative stress. Due to its affinity for thiol groups, cadmium may accumulate inside cells as cadmium-thiol complexes [32]. As a result, GSH levels fall, impacting cellular defenses against ROS [33]. Additionally, cadmium interferes with cellular protein breakdown, which is demonstrated by an increase in the number of ubiquitinated proteins. As a result, cadmium disrupts many cellular functions, including the antioxidant response [34][35]. Besides, ROS production by lead has been identified as a key mechanism underpinning lead poisoning. For example, the δ-aminolevulinic acid (ALA) dehydrase (ALAD) is affected by the presence of lead, leading to elevated ALA levels, which induces the production of ROS. The oxidation product of ALA may, in turn, cause DNA damage [36]. In addition, lead impacts the antioxidant defense mechanisms [37]. By blocking functional sulfhydryl groups in various enzymes, including SOD, CAT, glutathione peroxidase, and glucose-6-phosphate dehydrogenase, lead has been demonstrated to change antioxidant activity [37].
Oxidative stress and mitochondrial damage are intimately related. Thus, mitochondrial dysfunction may be linked to ASD [38][39][40][41][42][43]. Mitochondria oxidize glucose and fatty acids to produce ATP. In addition, the mitochondria play critical roles in calcium homeostasis and programmed cell death (apoptosis). They impact CNS neuronal functions such as synaptic plasticity and neurotransmitter release [44]. Brain cells are cells with a high energy requirement. Therefore, they have more mitochondria and are particularly vulnerable.
Children with ASD may have mitochondrial (mt) damage, which manifests as mtDNA over-replication, mtDNA deletions, and mitochondrial malfunction (lower mitochondrial-dependent oxygen consumption and increased hydrogen peroxide (H2O2) generation) [38][45]. It was reported that symptoms discovered as a result of mitochondrial malfunction coincide with those of ASD, suggesting that mitochondrial damage may contribute to the phenotype of ASD [46]. A reduced synaptic neurotransmitter release and improper calcium signaling due to mitochondrial malfunction have been proposed as potential pathomechanisms. Notably, plasma membrane calcium channels are impacted by mitochondria, which serve as calcium reserves [47].

2. Neuroinflammation

Numerous immunological disorders can arise from toxic metal exposure. In epidemiological research and mechanistic studies utilizing animal models, disorders of the immune system and inflammation have been linked to ASD. It has been demonstrated that lead, cadmium, and mercury directly influence gene expression. The altered genes included those that encode proteins key to regulating oxidative stress and inflammation, among others [48][49][50]. Furthermore, it was shown that lead and methylmercury could directly trigger glial reactivity [51], and a rise in ROS and BBB permeability may be a component of this. For example, mercury is concentrated in astrocytes and, to a lesser extent, in microglial cells inside the CNS [52][53], which causes these cells to become dysfunctional [54]. Notably, activated glial cells such as microglia and astrocytes release the proinflammatory cytokines Tumor Necrosis Factor (TNF), Interleukin (IL)-1, and IL-6 [55]. TNF, IL-1, and IL-6 are elevated in biosamples of individuals with ASD, and their levels positively correlate with ASD severity [56][57][58]. Animal studies have demonstrated that IL-6, in particular, may change synapse formation and plasticity [59][60].
In susceptible people, elevated mercury and lead levels result in increased production of proinflammatory cytokines and the development of autoantibodies even at low levels of chronic exposure [61][62][63]. For instance, one study discovered a correlation between increased blood levels of autoantibodies and increased mercury levels [64]. Neuronal cytoskeletal proteins, neurofilaments, and myelin basic protein (MBP) are among the proteins that lead and mercury-induced autoantibodies target [65].

3. Axonal Demyelination

Numerous studies have linked ASD to white matter abnormalities, including hypomyelination [66][67][68]. Neuronal axons in the CNS are myelinated when oligodendrocytes create myelin, a multi-lamellar membrane rich in lipids. Myelination is important in establishing connectivity in the developing brain. Toxic trace metals affect myelination. For example, lead exposure has been connected to disrupted connectivity [69][70]. Glial cells, including oligodendrocytes, take up lead [71][72]. A reduction in the activity of 2′,3′-Cyclic-nucleotide 3’-phosphodiesterase (CNPase) by lead, an enzyme that has been demonstrated to be essential for myelin formation, might be a factor explaining reduced myelinization [73]. The CNS white matter is also damaged by cadmium. It was shown that oligodendrocytes, and more so oligodendrocyte progenitors, are susceptible to cadmium. Cadmium toxicity was tied to excessive production of ROS, leading to oligodendrocyte death or dysfunction. In addition, MeHg toxicity is linked to the downregulation of MBP in pregnant and lactating rats [74]. MBP is essential for the construction and function of the myelin sheaths by oligodendrocytes and Schwann cells.

4. Competition with Essential Metals, Especially Zinc

By competing with essential metals such as calcium and zinc for protein binding, toxic metals can affect activities mediated by these metals. In particular, calcium and zinc are critical intracellular signaling ions bound by many proteins. For example, around 10% of the human genome encodes for zinc-binding proteins [75]. Zinc and lead may compete for the same protein binding sites [76][77]. Zinc and mercury were also discovered to interact, and cadmium can inhibit the transport of zinc and calcium, including the transfer of zinc to the fetus [78]. In turn, this will influence the activity of enzymes and second messengers and interfere with cellular signaling, transport, and metabolism. Additionally, cadmium should compete somewhat with magnesium, copper, and iron [79]. The disturbance of physiological processes mediated by metals, such as calcium and zinc, may be a major pathomechanism of toxic metals [80] and contribute to the abovementioned processes.
For example, myelination is a zinc-dependent process. A study on rhesus monkeys showed that maternal zinc deficiency causes the offspring’s myelin protein profiles to change [81]. Additionally, it was discovered that MBP, a target of autoantibodies generated by lead and mercury, is a zinc-binding protein, indicating a function for zinc in myelin compaction [82][83]. Further, in addition to promoting the production of free radicals, toxic metals, such as cadmium, lead, and mercury, may also compromise the antioxidant system by displacing essential metals from antioxidant enzymes such as Cu-Zn SOD. Lead also disrupts mitochondrial calcium and substitutes calcium in calcium signaling systems, altering Calmodulin and numerous downstream protein kinases [84]. Thereby, lead impedes synaptic signaling and vital cellular processes, such as proliferation and differentiation, for example, by changing the activity of the protein kinase C (PKC) enzyme. Lead also reduces the calcium-dependent release of neurotransmitter vesicles [85]. This can be a way that lead affects glutamatergic neurotransmission [86], which is also dependent on critical zinc-regulated synaptic proteins [87].
Given that zinc can be replaced or the levels of zinc lowered by toxic metals, some of the consequences of zinc deficiency may be imitated by toxic metal overload. Thus, prenatal zinc deficiency and heavy metal overload may be two sides of the same coin.

This entry is adapted from the peer-reviewed paper 10.3390/ijms24010308

References

  1. Kern, J.K.; Jones, A.M. Evidence of toxicity, oxidative stress, and neuronal insult in autism. J. Toxicol. Environ. Health B Crit. Rev. 2006, 9, 485–499.
  2. Chauhan, A.; Audhya, T.; Chauhan, V. Brain region-specific glutathione redox imbalance in autism. Neurochem. Res. 2012, 37, 1681–1689.
  3. Deth, R.; Muratore, C.; Benzecry, J.; Power-Charnitsky, V.A.; Waly, M. How environmental and genetic factors combine to cause autism: A redox/methylation hypothesis. Neurotoxicology 2008, 29, 190–201.
  4. Bjørklund, G.; Meguid, N.A.; El-Bana, M.A.; Tinkov, A.A.; Saad, K.; Dadar, M.; Hemimi, M.; Skalny, A.V.; Hosnedlová, B.; Kizek, R.; et al. Oxidative Stress in Autism Spectrum Disorder. Mol. Neurobiol. 2020, 57, 2314–2332.
  5. Manivasagam, T.; Arunadevi, S.; Essa, M.M.; SaravanaBabu, C.; Borah, A.; Thenmozhi, A.J.; Qoronfleh, M.W. Role of Oxidative Stress and Antioxidants in Autism. Adv. Neurobiol. 2020, 24, 193–206.
  6. Salim, S. Oxidative Stress and the Central Nervous System. J. Pharmacol. Exp. Ther. 2017, 360, 201–205.
  7. Knapp, L.T.; Klann, E. Role of reactive oxygen species in hippocampal long-term potentiation: Contributory or inhibitory? J. Neurosci. Res. 2002, 70, 1–7.
  8. Massaad, C.A.; Klann, E. Reactive oxygen species in the regulation of synaptic plasticity and memory. Antioxid. Redox Signal. 2011, 14, 2013–2054.
  9. Park, H.R.; Park, M.; Choi, J.; Park, K.Y.; Chung, H.Y.; Lee, J. A high-fat diet impairs neurogenesis: Involvement of lipid peroxidation and brain-derived neurotrophic factor. Neurosci. Lett. 2010, 482, 235–239.
  10. Gaschler, M.M.; Stockwell, B.R. Lipid peroxidation in cell death. Biochem. Biophys. Res. Commun. 2017, 482, 419–425.
  11. Ghanizadeh, A. Malondialdehyde, Bcl-2, superoxide dismutase and glutathione peroxidase may mediate the association of sonic hedgehog protein and oxidative stress in autism. Neurochem. Res. 2012, 37, 899–901.
  12. Saghazadeh, A.; Rezaei, N. Brain-Derived Neurotrophic Factor Levels in Autism: A Systematic Review and Meta-Analysis. J. Autism Dev. Disord. 2017, 47, 1018–1029.
  13. Pun, P.B.; Lu, J.; Moochhala, S. Involvement of ROS in BBB dysfunction. Free Radic. Res. 2009, 43, 348–364.
  14. Gu, Y.; Dee, C.M.; Shen, J. Interaction of free radicals, matrix metalloproteinases and caveolin-1 impacts blood-brain barrier permeability. Front. Biosci. Schol. Ed. 2011, 3, 1216–1231.
  15. Takahashi, T.; Shimohata, T. Vascular Dysfunction Induced by Mercury Exposure. Int. J. Mol. Sci. 2019, 20, 2435.
  16. Kasahara, E.; Inoue, M. Cross-talk between HPA-axis-increased glucocorticoids and mitochondrial stress determines immune responses and clinical manifestations of patients with sepsis. Redox Rep. 2015, 20, 1–10.
  17. Forder, J.P.; Tymianski, M. Postsynaptic mechanisms of excitotoxicity: Involvement of postsynaptic density proteins, radicals, and oxidant molecules. Neuroscience 2009, 158, 293–300.
  18. Bórquez, D.A.; Urrutia, P.J.; Wilson, C.; van Zundert, B.; Núñez, M.T.; González-Billault, C. Dissecting the role of redox signaling in neuronal development. J. Neurochem. 2016, 137, 506–517.
  19. Morris, G.; Puri, B.K.; Walker, A.J.; Berk, M.; Walder, K.; Bortolasci, C.C.; Marx, W.; Carvalho, A.F.; Maes, M. The compensatory antioxidant response system with a focus on neuroprogressive disorders. Prog. Neuropsychopharmacol. Biol. Psychiatry 2019, 95, 109708.
  20. Birben, E.; Sahiner, U.M.; Sackesen, C.; Erzurum, S.; Kalayci, O. Oxidative stress and antioxidant defense. World Allergy Organ J. 2012, 5, 9–19.
  21. Carocci, A.; Rovito, N.; Sinicropi, M.S.; Genchi, G. Mercury toxicity and neurodegenerative effects. Rev. Environ. Contam. Toxicol. 2014, 229, 1–18.
  22. Yin, Z.; Milatovic, D.; Aschner, J.L.; Syversen, T.; Rocha, J.B.; Souza, D.O.; Sidoryk, M.; Albrecht, J.; Aschner, M. Methylmercury induces oxidative injury, alterations in permeability and glutamine transport in cultured astrocytes. Brain Res. 2007, 1131, 1–10.
  23. Farina, M.; Aschner, M. Glutathione antioxidant system and methylmercury-induced neurotoxicity: An intriguing interplay. Biochim. Biophys. Acta Gen. Subj. 2019, 1863, 129285.
  24. Farina, M.; Rocha, J.B.; Aschner, M. Mechanisms of methylmercury-induced neurotoxicity: Evidence from experimental studies. Life Sci. 2011, 89, 555–563.
  25. Franco, J.L.; Posser, T.; Dunkley, P.R.; Dickson, P.W.; Mattos, J.J.; Martins, R.; Bainy, A.C.; Marques, M.R.; Dafre, A.L.; Farina, M. Methylmercury neurotoxicity is associated with inhibition of the antioxidant enzyme glutathione peroxidase. Free Radic. Biol. Med. 2009, 47, 449–457.
  26. Porciuncula, L.O.; Rocha, J.B.; Tavares, R.G.; Ghisleni, G.; Reis, M.; Souza, D.O. Methylmercury inhibits glutamate uptake by synaptic vesicles from rat brain. Neuroreport 2003, 14, 577–580.
  27. Reynolds, J.N.; Racz, W.J. Effects of methylmercury on the spontaneous and potassium-evoked release of endogenous amino acids from mouse cerebellar slices. Can. J. Physiol. Pharmacol. 1987, 65, 791–798.
  28. Moretto, M.B.; Funchal, C.; Santos, A.Q.; Gottfried, C.; Boff, B.; Zeni, G.; Pureur, R.P.; Souza, D.O.; Wofchuk, S.; Rocha, J.B. Ebselen protects glutamate uptake inhibition caused by methyl mercury but does not by Hg2+. Toxicology 2005, 214, 57–66.
  29. Vendrell, I.; Carrascal, M.; Vilaro, M.T.; Abian, J.; Rodriguez-Farre, E.; Sunol, C. Cell viability and proteomic analysis in cultured neurons exposed to methylmercury. Hum. Exp. Toxicol. 2007, 26, 263–272.
  30. Kritis, A.A.; Stamoula, E.G.; Paniskaki, K.A.; Vavilis, T.D. Researching glutamate-induced cytotoxicity in different cell lines: A comparative/collective analysis/study. Front. Cell Neurosci. 2015, 9, 91.
  31. Aschner, M.; Yao, C.P.; Allen, J.W.; Tan, K.H. Methylmercury alters glutamate transport in astrocytes. Neurochem. Int. 2000, 37, 199–206.
  32. Figueiredo-Pereira, M.E.; Yakushin, S.; Cohen, G. Disruption of the intracellular sulfhydryl homeostasis by cadmium-induced oxidative stress leads to protein thiolation and ubiquitination in neuronal cells. J. Biol. Chem. 1998, 273, 12703–12709.
  33. Bertin, G.; Averbeck, D. Cadmium: Cellular effects, modifications of biomolecules, modulation of DNA repair and genotoxic consequences (a review). Biochimie 2006, 88, 1549–1559.
  34. Dong, S.; Shen, H.M.; Ong, C.N. Cadmium-induced apoptosis and phenotypic changes in mouse thymocytes. Mol. Cell Biochem. 2001, 222, 11–20.
  35. Yang, P.M.; Chiu, S.J.; Lin, K.A.; Lin, L.Y. Effect of cadmium on cell cycle progression in Chinese hamster ovary cells. Chem. Biol. Interact. 2004, 149, 125–136.
  36. Lopes, A.C.; Peixe, T.S.; Mesas, A.E.; Paoliello, M.M. Lead Exposure and Oxidative Stress: A Systematic Review. Rev. Environ. Contam. Toxicol. 2016, 236, 193–238.
  37. Patra, R.C.; Rautray, A.K.; Swarup, D. Oxidative stress in lead and cadmium toxicity and its amelioration. Vet. Med. Int. 2011, 2011, 457327.
  38. Giulivi, C.; Zhang, Y.F.; Omanska-Klusek, A.; Ross-Inta, C.; Wong, S.; Hertz-Picciotto, I.; Tassone, F.; Pessah, I.N. Mitochondrial dysfunction in autism. JAMA 2010, 304, 2389–2396.
  39. Dhillon, S.; Hellings, J.A.; Butler, M.G. Genetics and mitochondrial abnormalities in autism spectrum disorders: A review. Curr. Genom. 2011, 12, 322–332.
  40. Castora, F.J. Mitochondrial function and abnormalities implicated in the pathogenesis of ASD. Prog. Neuropsychopharmacol. Biol. Psychiatry 2019, 92, 83–108.
  41. Griffiths, K.K.; Levy, R.J. Evidence of Mitochondrial Dysfunction in Autism: Biochemical Links, Genetic-Based Associations, and Non-Energy-Related Mechanisms. Oxid. Med. Cell Longev. 2017, 2017, 4314025.
  42. Valiente-Pallejà, A.; Torrell, H.; Muntané, G.; Cortés, M.J.; Martínez-Leal, R.; Abasolo, N.; Alonso, Y.; Vilella, E.; Martorell, L. Genetic and clinical evidence of mitochondrial dysfunction in autism spectrum disorder and intellectual disability. Hum. Mol. Genet. 2018, 27, 891–900.
  43. Rossignol, D.A.; Frye, R.E. Mitochondrial dysfunction in autism spectrum disorders: A systematic review and meta-analysis. Mol. Psychiatry 2012, 17, 290–314.
  44. Devine, M.J.; Kittler, J.T. Mitochondria at the neuronal presynapse in health and disease. Nat. Rev. Neurosci. 2018, 19, 63–80.
  45. Varga, N.Á.; Pentelényi, K.; Balicza, P.; Gézsi, A.; Reményi, V.; Hársfalvi, V.; Bencsik, R.; Illés, A.; Prekop, C.; Molnár, M.J. Mitochondrial dysfunction and autism: Comprehensive genetic analyses of children with autism and mtDNA deletion. Behav. Brain Funct. 2018, 14, 4.
  46. Frye, R.E.; Rossignol, D.A. Mitochondrial dysfunction can connect the diverse medical symptoms associated with autism spectrum disorders. Pediatr. Res. 2011, 69, 41R–47R.
  47. Napolioni, V.; Persico, A.M.; Porcelli, V.; Palmieri, L. The mitochondrial aspartate/glutamate carrier AGC1 and calcium homeostasis: Physiological links and abnormalities in autism. Mol. Neurobiol. 2011, 44, 83–92.
  48. Bartosiewicz, M.J.; Jenkins, D.; Penn, S.; Emery, J.; Buckpitt, A. Unique gene expression patterns in liver and kidney associated with exposure to chemical toxicants. J. Pharmacol. Exp. Ther. 2001, 297, 895–905.
  49. Eyssen-Hernandez, R.; Ladoux, A.; Frelin, C. Differential regulation of cardiac heme oxygenase-1 and vascular endothelial growth factor mRNA expressions by hemin, heavy metals, heat shock and anoxia. FEBS Lett. 1996, 382, 229–233.
  50. Breton, J.; Le Clère, K.; Daniel, C.; Sauty, M.; Nakab, L.; Chassat, T.; Dewulf, J.; Penet, S.; Carnoy, C.; Thomas, P.; et al. Chronic ingestion of cadmium and lead alters the bioavailability of essential and heavy metals, gene expression pathways and genotoxicity in mouse intestine. Arch. Toxicol. 2013, 87, 1787–1795.
  51. Monnet-Tschudi, F.; Zurich, M.G.; Boschat, C.; Corbaz, A.; Honegger, P. Involvement of environmental mercury and lead in the etiology of neurodegenerative diseases. Rev. Environ. Health 2006, 21, 105–117.
  52. Shanker, G.; Syversen, T.; Aschner, M. Astrocyte-mediated methylmercury neurotoxicity. Biol. Trace Elem. Res. 2003, 95, 1–10.
  53. Tiffany-Castiglion, E.; Qian, Y. Astroglia as metal depots: Molecular mechanisms for metal accumulation, storage and release. Neurotoxicology 2001, 22, 577–592.
  54. Pieper, I.; Wehe, C.A.; Bornhorst, J.; Ebert, F.; Leffers, L.; Holtkamp, M.; Höseler, P.; Weber, T.; Mangerich, A.; Bürkle, A.; et al. Mechanisms of Hg species induced toxicity in cultured human astrocytes: Genotoxicity and DNA-damage response. Metallomics 2014, 6, 662–671.
  55. Vargas, D.L.; Nascimbene, C.; Krishnan, C.; Zimmerman, A.W.; Pardo, C.A. Neuroglial activation and neuroinflammation in the brain of patients with autism. Ann. Neurol. 2005, 57, 67–81.
  56. Siniscalco, D.; Schultz, S.; Brigida, A.L.; Antonucci, N. Inflammation and Neuro-Immune Dysregulations in Autism Spectrum Disorders. Pharmaceuticals 2018, 11, 56.
  57. Theoharides, T.C.; Tsilioni, I.; Patel, A.B.; Doyle, R. Atopic diseases and inflammation of the brain in the pathogenesis of autism spectrum disorders. Transl. Psychiatry 2016, 6, e844.
  58. Wei, H.; Alberts, I.; Li, X. Brain IL-6 and autism. Neuroscience 2013, 252, 320–325.
  59. Wei, H.; Chadman, K.K.; McCloskey, D.P.; Sheikh, A.M.; Malik, M.; Brown, W.T.; Li, X. Brain IL-6 elevation causes neuronal circuitry imbalances and mediates autism-like behaviors. Biochim. Biophys. Acta 2012, 1822, 831–842.
  60. Wei, H.; Mori, S.; Hua, K.; Li, X. Alteration of brain volume in IL-6 overexpressing mice related to autism. Int. J. Dev. Neurosci. 2012, 30, 554–559.
  61. Pollard, K.M.; Cauvi, D.M.; Toomey, C.B.; Hultman, P.; Kono, D.H. Mercury-induced inflammation and autoimmunity. Biochim. Biophys. Acta Gen. Subj. 2019, 1863, 129299.
  62. Mishra, K.P. Lead exposure and its impact on immune system: A review. Toxicol. In Vitro 2009, 23, 969–972.
  63. Bjørklund, G.; Peana, M.; Dadar, M.; Chirumbolo, S.; Aaseth, J.; Martins, N. Mercury-induced autoimmunity: Drifting from micro to macro concerns on autoimmune disorders. Clin. Immunol. 2020, 213, 108352.
  64. Motts, J.A.; Shirley, D.L.; Silbergeld, E.K.; Nyland, J.F. Novel biomarkers of mercury-induced autoimmune dysfunction: A cross-sectional study in Amazonian Brazil. Environ. Res. 2014, 132, 12–18.
  65. El-Fawal, H.A.; Waterman, S.J.; De Feo, A.; Shamy, M.Y. Neuroimmunotoxicology: Humoral assessment of neurotoxicity and autoimmune mechanisms. Environ. Health Perspect. 1999, 107 (Suppl. 5), 767–775.
  66. Lazar, M.; Miles, L.M.; Babb, J.S.; Donaldson, J.B. Axonal deficits in young adults with High Functioning Autism and their impact on processing speed. Neuroimage Clin. 2014, 4, 417–425.
  67. Shen, H.Y.; Huang, N.; Reemmer, J.; Xiao, L. Adenosine Actions on Oligodendroglia and Myelination in Autism Spectrum Disorder. Front. Cell Neurosci. 2018, 12, 482.
  68. Malara, M.; Lutz, A.K.; Incearap, B.; Bauer, H.F.; Cursano, S.; Volbracht, K.; Lerner, J.J.; Pandey, R.; Delling, J.P.; Ioannidis, V.; et al. SHANK3 deficiency leads to myelin defects in the central and peripheral nervous system. Cell Mol. Life Sci. 2022, 79, 371.
  69. Thomason, M.E.; Hect, J.L.; Rauh, V.A.; Trentacosta, C.; Wheelock, M.D.; Eggebrecht, A.T.; Espinoza-Heredia, C.; Burt, S.A. Prenatal lead exposure impacts cross-hemispheric and long-range connectivity in the human fetal brain. Neuroimage 2019, 191, 186–192.
  70. Cecil, K.M.; Brubaker, C.J.; Adler, C.M.; Dietrich, K.N.; Altaye, M.; Egelhoff, J.C.; Wessel, S.; Elangovan, I.; Hornung, R.; Jarvis, K.; et al. Decreased brain volume in adults with childhood lead exposure. PLoS Med. 2008, 5, e112.
  71. Lidsky, T.I.; Schneider, J.S. Lead neurotoxicity in children: Basic mechanisms and clinical correlates. Brain 2003, 126, 5–19.
  72. Lindahl, L.S.; Bird, L.; Legare, M.E.; Mikeska, G.; Bratton, G.R.; Tiffany-Castiglioni, E. Differential ability of astroglia and neuronal cells to accumulate lead: Dependence on cell type and on degree of differentiation. Toxicol. Sci. 1999, 50, 236–243.
  73. Dabrowska-Bouta, B.; Sulkowski, G.; Walski, M.; Struzyńska, L.; Lenkiewicz, A.; Rafałowska, U. Acute lead intoxication in vivo affects myelin membrane morphology and CNPase activity. Exp. Toxicol. Pathol. 2000, 52, 257–263.
  74. Da Silva, D.C.B.; Bittencourt, L.O.; Baia-da-Silva, D.C.; Chemelo, V.S.; Eiró-Quirino, L.; Nascimento, P.C.; Silva, M.C.F.; Freire, M.A.M.; Gomes-Leal, W.; Crespo-Lopez, M.E.; et al. Methylmercury Causes Neurodegeneration and Downregulation of Myelin Basic Protein in the Spinal Cord of Offspring Rats after Maternal Exposure. Int. J. Mol. Sci. 2022, 23, 3777.
  75. Andreini, C.; Banci, L.; Bertini, I.; Rosato, A. Counting the zinc-proteins encoded in the human genome. J. Proteome Res. 2006, 5, 196–201.
  76. Flora, S.J.; Singh, S.; Tandon, S.K. Thiamine and zinc in prevention or therapy of lead intoxication. J. Int. Med. Res. 1989, 17, 68–75.
  77. Flora, S.J.; Kumar, D.; Das Gupta, S. Interaction of zinc, methionine or their combination with lead at gastrointestinal or post-absorptive level in rats. Pharmacol. Toxicol. 1991, 68, 3–7.
  78. Kippler, M.; Hoque, A.M.; Raqib, R.; Ohrvik, H.; Ekström, E.C.; Vahter, M. Accumulation of cadmium in human placenta interacts with the transport of micronutrients to the fetus. Toxicol. Lett. 2010, 192, 162–168.
  79. Moulis, J.M. Cellular mechanisms of cadmium toxicity related to the homeostasis of essential metals. Biometals 2010, 23, 877–896.
  80. Bressler, J.P.; Goldstein, G.W. Mechanisms of lead neurotoxicity. Biochem. Pharmacol. 1991, 41, 479–484.
  81. Liu, H.; Oteiza, P.I.; Gershwin, M.E.; Golub, M.S.; Keen, C.L. Effects of maternal marginal zinc deficiency on myelin protein profiles in the suckling rat and infant rhesus monkey. Biol. Trace Elem. Res. 1992, 34, 55–66.
  82. Bakhti, M.; Aggarwal, S.; Simons, M. Myelin architecture: Zippering membranes tightly together. Cell Mol. Life Sci. 2014, 71, 1265–1277.
  83. Tsang, D.; Tsang, Y.S.; Ho, W.K.; Wong, R.N. Myelin basic protein is a zinc-binding protein in brain: Possible role in myelin compaction. Neurochem. Res. 1997, 22, 811–819.
  84. Bressler, J.; Kim, K.A.; Chakraborti, T.; Goldstein, G. Molecular mechanisms of lead neurotoxicity. Neurochem. Res. 1999, 24, 595–600.
  85. Lasley, S.M.; Green, M.C.; Gilbert, M.E. Influence of exposure period on in vivo hippocampal glutamate and GABA release in rats chronically exposed to lead. Neurotoxicology 1999, 20, 619–629.
  86. Neal, A.P.; Stansfield, K.H.; Worley, P.F.; Thompson, R.E.; Guilarte, T.R. Lead exposure during synaptogenesis alters vesicular proteins and impairs vesicular release: Potential role of NMDA receptor-dependent BDNF signaling. Toxicol. Sci. 2010, 116, 249–263.
  87. Grabrucker, A.M.; Knight, M.J.; Proepper, C.; Bockmann, J.; Joubert, M.; Rowan, M.; Nienhaus, G.U.; Garner, C.C.; Bowie, J.U.; Kreutz, M.R.; et al. Concerted action of zinc and ProSAP/Shank in synaptogenesis and synapse maturation. EMBO J. 2011, 30, 569–581.
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